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What Is Mild Traumatic Brain Injury? Translational Definitions to Guide Translational Research
C H A P T E R
1 What Is Mild Traumatic Brain Injury? Translational Definitions to Guide Translational Research Michael E. Hoffer, MD1 and Carey D. Balaban, PhD2 1
Department of Otolaryngology and Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, United States 2Departments of Otolaryngology, Neurobiology, Communication Sciences & Disorders, and Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
Mild traumatic brain injury (mTBI) is a common public health concern that has garnered increased attention in both the lay press and medical literature. mTBI/concussion is particularly common in the military where up to 20% of individuals deployed to Southwest Asia have been affected.1 7 In the US Military, between 2000 and 2016, 361,092 active duty service members suffered from TBI, ranging from mild (82% of cases) to severe or penetrating.2 However, the diagnosis is not restricted to the military; recent literature reports that the incidence and prevalence of TBI in the civilian population is increasing.8 A number of reports that focused on selected populations, such as high school athletes9 or emergency departments (EDs) over limited time frames10,11 give estimates of the relative prevalence of mTBI in different populations. For example, Marin et al.12 used the Nationwide Emergency Department Sample to investigate trends of visits to EDs for TBI between 2006 and 2010. The data, pooled from a sample of 950 hospitals, showed a sharp increase in the weighted rates of ED visits from 2006 to 2010. In 2006, there were 637 TBI visits per 100,000 ED visits and by 2010 this figure was up to 822 per 100,000, with a disproportionate increase in the number of reported mTBI or concussion visits.13 It is noteworthy that there was a commensurate increase in the number of peer-viewed journal publications in the ISI Web of Science with “mild traumatic brain” as a term in the title, from 27 in 2006, to 44 in 2010, 49 in 2011, and 158 in 2017 (Fig. 1.1). One may suggest that the increased number of visits reflected an increased recognition of a common phenomenon rather than a sudden increase in prevalence of mTBI. Despite the recent focus on the prevalence of this disorder in the media, the question of the establishment of precise, mechanistically anchored criteria for mTBI remains Neurosensory Disorders in Mild Traumatic Brain Injury DOI: https://doi.org/10.1016/B978-0-12-812344-7.00001-7
3
Copyright © 2019 Elsevier Inc. All rights reserved.
4
1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
FIGURE 1.1 Peer reviewed research publications by year.
challenging because it requires that the signs and symptoms are linked temporally to a traumatic event as the proximate cause. The National Institute of Health (NIH) has a very straightforward definition: “Traumatic brain injury (TBI), a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain.”14 While this seems straightforward, the definition of a “sudden trauma” can be the subject of debate as its causal linkage to acute, subacute, and chronic symptoms can be problematic. For the purposes of this book we will broadly define the “sudden trauma” as any force (or “directed energy”) that causes the brain itself or the contents of the brain to be altered sufficiently to cause physiological dysfunction, biochemical dysfunction, or structural alterations. There is some evidence to suggest that there are significant differences in the mode of TBI presentation based on etiology, but these differences still produce effects that are within a spectrum of those that can be seen in TBI irrespective of the etiology.15,16 Despite the debate, the NIH definition was crafted pragmatically to allow general acceptance. Initially TBI was broadly divided into mild, moderate, and severe using the wellestablished Glasgow Coma Scale (GCS) as an acute metric.15 While this method seems straightforward given the objective nature of the GCS, this criterion has three main shortcomings. Firstly, most of the individuals with GCS scores less than 13 have some form of severe TBI, meaning the remaining individuals are compressed into a fairly tight range of 13 15 with the vast majority of these being 15. As such the numerical value of the GCS seems ideally suited to distinguish severe from mild or moderate TBI, but this distinction is generally clinically apparent. Beyond that, the scale provides little value for individuals with mild TBI. Secondly, the vast majority of individuals with mTBI do not receive a GCS at the time of injury. Hence, the value of any subsequent or “retrospective” GCS, especially days later, is suspect at best. Finally, individuals with mTBI have a range of sequelae and different outcomes despite having a GCS of 14 or 15; as such, the value does little to distinguish patients on the basis of signs and symptoms that characterize the functional pathology.
I. DEFINING MILD TBI
THE NIH DEFINITION
5
THE NIH DEFINITION A person with a mild TBI may remain conscious or may experience a loss of consciousness for a few seconds or minutes. Other symptoms of mild TBI include headache, confusion, lightheadedness, dizziness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, a change in sleep patterns, behavioral or mood changes, and trouble with memory, concentration, attention, or thinking.
This description incorporates three generally accepted definitions of mTBI that have been published over time.17 In 1993 the American Congress of Rehabilitation Medicine (ACRM) described mTBI as an alteration of brain function caused by an external force with one of more to the following: (1) loss of consciousness (LOC) of 0 30 minutes; (2) posttraumatic amnesia (PTA) lasting 0 24 hours; (3) focal neurologic deficits may or may not be transient; and (4) alteration of mental state at the time of the accident (confusion, disorientation, slow-thinking).18 In 2003, the Centers for Disease Control and Prevention (CDC) offered a slightly less specific classification in which an individual must have any period of observed or self-reported transient confusion, disorientation, or impaired consciousness around the time of a head injury with LOC lasting 0 30 minutes.19 In 2009, the Department of Defense (DoD) established guidelines similar to the ACRM guidelines, but added that the alteration of consciousness (AOC) lasts less than 24 hours.20 The DoD updated this definition in 2016 and defined mTBI as: “traumatically induced structural or physiologic disruption of brain function as a result of an external force with new onset or worsening of at least one of the following: loss or decreased level of consciousness, (LOC , 30 minutes, AOC ,24 hours), PTA (,1 day), alteration in mental status (e.g., confusion, disorientation, etc.), Neurological deficit (weakness, loss of balance, sensory losses, etc.)." They added that the GCS should be 13 15 and structural imaging should be normal.21 To summarize colloquially, mild TBI is diagnosed by a documented directed energy event that results in the patient reporting symptoms or displaying nonlocalizing signs of being “not quite right.” Complicating these definitions of mTBI include the subcategories of “complicated mTBI” and concussion. Some investigators use the term “complicated mTBI” when the mTBI symptoms are accompanied by positive findings with radiologic imaging.22 24 The difficulty with this diagnosis is that imaging changes over time. The original definition of “complicated mTBI” relied on CT scans that showed abnormalities; there is some evidence that these individuals followed a course more similar to moderate TBI.23,24 Therefore, positive CT scan findings often shift diagnosis to the moderate TBI group. However, more modern imaging, including traditional MRI, fMRI, high Tesla MRI, and other scans, do detect abnormalities in some individuals and it is unclear whether these abnormalities have any longer term clinical or functional implications that distinguish them from symptomatic, but radiologically negative, patients. The term concussion is often used synonymously with mTBI. It is likely the case that concussion is simply a type of mTBI. While it is usually on the milder side of the spectrum, the short-term and long-term consequences provide little basis for distinguishing between these terms. The diagnostic criteria for concussion in athletes has been examined by a group of experts meeting every other year who have published updated guidelines after each of these meetings.25,26
I. DEFINING MILD TBI
6
1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
While the diagnosis of mTBI and concussion remain difficult to differentiate, postconcussion syndrome has an acceptable definition provide for the International Classification of Diseases 10th edition (ICD-10).27 This World Health organization-accepted medical definition requires the following: (1) The syndrome follows a head trauma, and (2) The individual present with at least three of the following eight symptoms: headache, dizziness, fatigue, irritability, difficulty concentrating, memory impairment, insomnia, and intolerance to stress, emotion, or alcohol. Because this definition of concussion appears to be synonymous with mTBI, there seems to be little value in assigning this term only to the “mildest” cases until there is a more objective and precise way of making this determination. We must acknowledge that: the diagnosis of mTBI or concussion requires the presumption of a causal link to a documented traumatic event. The dilemma becomes most evident when a patient appears for a workman’s compensation examination, reporting a plethora of nonspecific symptoms that could indicate mTBI. The patient attributes the symptoms to an unwitnessed head-bump several weeks earlier. If one subjects the patient to a large battery of neurologic tests and advanced imaging, what is the likelihood that incidental chronic findings might be misattributed to an undocumented traumatic event? These considerations obviously mandate a healthy skepticism prior to asserting post hoc diagnoses from unknown cranially directed energy exposures. Although we can document signs and symptoms that appear after documented traumatic events, the observations of a similar clinical syndrome are insufficient to substantiate a causal claim regarding an unverified (or assumed) traumatic incident. The structure of symptom complexes in acute mTBI suggests that integrative, objective diagnosis should be tractable. For example, principal component analysis of a standard 22item symptom scale showed acute mTBI and control subjects differed by a posttraumatic migraine/headache symptom cluster, a dizziness/mild cognitive impairment symptom cluster, an emotional lability symptom cluster, a cervicogenic (neck pain fatigue malaise) symptom cluster, and nausea.28 Unfortunately, attempts to devise integrative approaches to overall objective diagnosis of mTBI signs have been complicated by several issues. Firstly, the symptom clusters do not unambiguously point to localized injury. Secondly, concerns have been raised about the accuracy of symptom self-reports, which seem to be inherently unreliable and unstable in patients with mTBI.29,30 For example, symptom reports may be exaggerated or understated (denial) for secondary gain, which can produce symptom complex component scores on both tails of the distributions in acute mTBI patients (Hoffer et al. PLoS One, symptom complex paper) Thirdly, the heterogeneous presentation of mTBI makes unified objective diagnostic criteria difficult to identify. The presentation can vary with small changes in the magnitude or direction of the force, by the subjects’ past medical and particularly, past head injury, history, and by a variety of other factors including anatomic and genetic differences. Fourthly, the manifestations of the mTBI change over time, based on external environmental and epigenetic influences that are independent of the trauma and, again, affect every individual differently. Fifthly, mTBI in an individual case may involve a number of parallel, but very small injuries, in more than one location in the brain or intracranial sensory organs Sixthly, home remedies, spontaneous compensation, and variations in treatment regimens complicate the subacute and chronic presentations. These factors may contribute to the conclusion that the trend of attempts to classify the disorder in terms of common objective features has been fraught with difficulty.15
I. DEFINING MILD TBI
REFERENCES
7
Currently, there is no definitive path to make a “ground-truth” diagnosis of a mTBI without a validated, temporally proximate acute application of external force. The problem obviously becomes exacerbated as the latency increases between a suspected event and presentation of the patient. Criteria have been established by a variety of organizations, but there remains debate as to how best to apply these criteria. Moreover, there remains debate over what constitutes an “external force” and the latency between the event and onset of signs and symptoms. Most investigators agree that classifying TBI into mild, moderate, and severe is a highly imprecise medical classification system.15,31 These researchers and clinicians advocate a more deliberate and objective approach to diagnosis that takes into account temporal sequences of symptoms, objective neurological signs, the recovery trajectory, and long-term outcomes. As a pragmatic matter, there is no justification for eliminating the diagnostic term mTBI until better alternatives for differentiated diagnosis are available. We believe a reasonable diagnostic criterion is very similar to the most recent criteria proposed by the DoD/VA.21 Our “operational definition” is that an individual: (1) suffers an impact to the head; (2) has LOC (,30 minutes) or AOC (,24 hours); and (3) presents with one of the symptoms including, but not limited to, balance disorder, hearing disorder, headache, visual changes, alteration in mental status, and sleep disturbance. This diagnostic criterion seems to brings together the criteria proposed and listed above and is in concordance with general clinical practice. The difficulty in developing a definition for mTBI is magnified when attempting to utilize this definition for translational research. Research on animal models is vitally important to both develop new diagnostic and treatment algorithms, as well as to translate basic science findings into human use. Unfortunately, most rodent animal models seek to create a very homogenous pattern of injury, but are attempting to model a disorder that is very heterogeneous in humans.32 In addition, physical damage that would be termed severe in a humans produces only modest behavioral signs in rodent animal models. The ability to reproduce rodent analogues of human psychological and social impacts of mTBI are far from incontrovertible. This is certainly an area where a more precise definition based on the site of injury or neuropathological findings would be helpful. That being said, those set of conditions (site of injury, neuropathological findings, etc.) are likely to be just as heterogeneous in affected humans as the current symptom spectrum of mTBI, therefore, such precision may not allow for better translational research. No matter how it is defined, we believe that the term mTBI in particular and TBI in general must be “destigmatized.” Too often there is serious debate over whether an individual has “TBI” when it is clear that the individual had a blow to the head, suffered and AOC, and has symptoms. The individual clearly has a brain injury that should be labeled as “TBI.” This label implies nothing about short-term or even long-term consequences, nor should it be reserved for only a particular type of brain injury or particular class of individuals.
References 1. https://www.rand.org/news/press/2008/04/17.html. 2. Defense Medical Surveillance System (DMMS)S. DoD numbers for traumatic brain injury—worldwide: defense and veterans brain injury center (DVBIC). 2017.
I. DEFINING MILD TBI
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1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
3. Hoffer ME, Balaban C, Gottshall K, Balough BJ, Maddox MR, et al. Blast exposure: vestibular consequences and associated characteristics. Otol Neurotol 2010;31:232 6. 4. Scherer MR, Burrows H, Pinto R, Littlefield P, French LM, Tarbett AK, et al. Evidence of central and peripheral vestibular pathology in blast-related traumatic brain injury. Otol Neurotol 2011;24. 5. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med 2008;358:453 63. 6. Terrio H, Brenner LA, Ivins BJ, Cho JM, Helmick K, et al. Traumatic brain injury screening: preliminary findings in a US Army Brigade Combat Team. J Head Trauma Rehabil 2009;24:14 23. 7. Hosek B. How is deployment to Iraq and Afghanistan affecting U.S. service members and their families? An overview of early RAND research on the topic. Santa Monica, CA: RAND Corporation; 2011. 8. http://www.cdc.gov/TraumaticBrainInjury/index.html. 9. Powell JW, Barber-Foss KD. Traumatic brain injury in high school athlete. JAMA 1999;282(10):958 63. Available from: https://doi.org/10.1001/jama.282.10.958. 10. Guerrero JL, Thurman DJ, Sniezek JE. Emergency department visits associated with traumatic brain injury: United States, 1995 1996. Brain Inj 2000;14(2):181 6. 11. Kerr ZY, Harmon KJ, Marshall SW, Proescholdbell SK, Waller AE. The epidemiology of traumatic brain injuries treated in emergency departments in North Carolina, 2010 2011. N C Med J 2014;75(1):8 14. 12. Marin JR, Weaver MD, Yealy DM, Mannix RC. Trends in visits for traumatic brain injury to emergency departments in the United States. JAMA 2014;311(18):1917 19. Available from: https://doi.org/10.1001/ jama.2014.3979. 13. Lagbas C, Bazargan-Hejazi S, Shaheen M, Kermah D, Pan D. Traumatic brain injury related hospitalization and mortality in California. Biomed Res Int 2013;143092. Available from: https://doi.org/10.1155/2013/ 143092. Epub November 13, 2013. 14. https://www.ninds.nih.gov/Disorders/All-Disorders/Traumatic-Brain-Injury-Information-Page. 15. Hawryluk GW, Manley GT. Classification of traumatic brain injury: past, present, and future. Handb Clin Neurol 2015;127:15 21. Available from: https://doi.org/10.1016/B978-0-444-52892-6.00002-7. Review. PubMed PMID: 25702207. 16. Mendez MF, Owens EM, Reza Berenji G, Peppers DC, Liang LJ, Licht EA. Mild traumatic brain injury from primary blast vs. blunt forces: post-concussion consequences and functional neuroimaging. NeuroRehabilitation 2013;32(2):397 407. Available from: https://doi.org/10.3233/NRE-130861. PubMed PMID: 23535805. 17. Katz D, Sara IC, Michael PA. Chapter 9. Mild traumatic brain injury. Handb Clin Neurol 2015;127C:131 56. Available from: https://doi.org/10.1016/B978-0-444-52892-6.00009-X. 18. American Congress of Rehabilitation Medicine, Brain Injury Interdisciplinary Special Interest Group, Disorders of Consciousness Task Force. Definition of mild traumatic brain injury. J Head Trauma Rehabil 1993;8:86 7. 19. National Center for Injury Prevention and Control. Report to congress on mild traumatic brain injury in the United States: steps to prevent a serious public health problem. Atlanta, GA: Centers for Disease Control and Prevention; 2003. 20. Department of Veterans Affairs. Clinical practice guideline: management of concussion/mild traumatic brain injury. Washington, DC: Department of Veterans Affairs, DOD; 2009. 21. https://www.healthquality.va.gov/guidelines/Rehab/mtbi/mTBICPGFullCPG50821816.pdf. 22. Williams DH, Levin HS, Eisenberg HM. Mild head injury classification. Neurosurgery 1990;27:422 8. 23. Iverson GL. Complicated vs uncomplicated mild traumatic brain injury: acute neuropsychological outcome. Brain Inj 2006;20:1335 44. 24. Kashluba S, Hanks RA, Casey JE, et al. Neuropsychologic and functional outcome after complicated mild traumatic brain injury. Arch Phys Med Rehabil 2008;89:904 11. 25. McCrory P, Meeuwisse W, Johnston K, et al. Consensus statement on Concussion in Sport, 3rd International Conference on Concussion in Sport held in Zurich, November 2008. Clin J Sport Med 2009;19:185 200. 26. McCrory P, Meeuwisse W, Dvoˇra´k J, Aubry M, Bailes J, Broglio S, et al. Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med 2017;51(11):838 47. Available from: https://doi.org/10.1136/bjsports-2017-097699. Epub 2017 Apr 26. PubMed PMID: 28446457. 27. http://www.who.int/classifications/icd/icdonlineversions/en/
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REFERENCES
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28. Hoffer ME, Szczupak M, Kiderman A, Crawford J, Murphy S, Marshall K, Pelusso C, Balaban C. Neurosensory symptom complexes after acute mild traumatic brain injury. PLoS One 2016;11(1). Available from: https://doi.org/10.1371/journal.pone.0146039. , https:e0146039. . , eCollection 2016. 29. Spencer RJ, Drag LL, Walker SJ, Bieliauskas LA. Self-reported cognitive symptoms following mild traumatic brain injury are poorly associated with neuropsychological performance in OIF/OEF veterans. J Rehabil Res Dev 2010;47(6):521 30 PubMed PMID: 20848365. 30. Waddington GS. Self report balance status is not reliable post concussion. J Sci Med Sport 2017;20(11):963. Available from: https://doi.org/10.1016/j.jsams.2017.09.004. PubMedPMID: 28927553. 31. McCrory P, Feddermann-Demont N, Dvoˇra´k J, Cassidy JD, McIntosh A, Vos PE Echemendia RJ, et al. What is the definition of sports-related concussion: a systematic review. Br J Sports Med 2017;51(11):877 87. Available from: https://doi.org/10.1136/bjsports-2016-097393. Review. PubMed PMID: 29098981. 32. Bolouri H, Zetterberg H. Animal models for concussion: molecular and cognitive assessments—relevance to sport and military concussions. In: Kobeissy FH, editor. Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects. Boca Raton, FL: CRC Press/Taylor & Francis; 2015. Chapter 46. PubMed PMID: 26269898.
I. DEFINING MILD TBI
1 What Is Mild Traumatic Brain Injury? Translational Definitions to Guide Translational Research Michael E. Hoffer, MD1 and Carey D. Balaban, PhD2 1
Department of Otolaryngology and Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, United States 2Departments of Otolaryngology, Neurobiology, Communication Sciences & Disorders, and Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
Mild traumatic brain injury (mTBI) is a common public health concern that has garnered increased attention in both the lay press and medical literature. mTBI/concussion is particularly common in the military where up to 20% of individuals deployed to Southwest Asia have been affected.1 7 In the US Military, between 2000 and 2016, 361,092 active duty service members suffered from TBI, ranging from mild (82% of cases) to severe or penetrating.2 However, the diagnosis is not restricted to the military; recent literature reports that the incidence and prevalence of TBI in the civilian population is increasing.8 A number of reports that focused on selected populations, such as high school athletes9 or emergency departments (EDs) over limited time frames10,11 give estimates of the relative prevalence of mTBI in different populations. For example, Marin et al.12 used the Nationwide Emergency Department Sample to investigate trends of visits to EDs for TBI between 2006 and 2010. The data, pooled from a sample of 950 hospitals, showed a sharp increase in the weighted rates of ED visits from 2006 to 2010. In 2006, there were 637 TBI visits per 100,000 ED visits and by 2010 this figure was up to 822 per 100,000, with a disproportionate increase in the number of reported mTBI or concussion visits.13 It is noteworthy that there was a commensurate increase in the number of peer-viewed journal publications in the ISI Web of Science with “mild traumatic brain” as a term in the title, from 27 in 2006, to 44 in 2010, 49 in 2011, and 158 in 2017 (Fig. 1.1). One may suggest that the increased number of visits reflected an increased recognition of a common phenomenon rather than a sudden increase in prevalence of mTBI. Despite the recent focus on the prevalence of this disorder in the media, the question of the establishment of precise, mechanistically anchored criteria for mTBI remains Neurosensory Disorders in Mild Traumatic Brain Injury DOI: https://doi.org/10.1016/B978-0-12-812344-7.00001-7
3
Copyright © 2019 Elsevier Inc. All rights reserved.
4
1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
FIGURE 1.1 Peer reviewed research publications by year.
challenging because it requires that the signs and symptoms are linked temporally to a traumatic event as the proximate cause. The National Institute of Health (NIH) has a very straightforward definition: “Traumatic brain injury (TBI), a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain.”14 While this seems straightforward, the definition of a “sudden trauma” can be the subject of debate as its causal linkage to acute, subacute, and chronic symptoms can be problematic. For the purposes of this book we will broadly define the “sudden trauma” as any force (or “directed energy”) that causes the brain itself or the contents of the brain to be altered sufficiently to cause physiological dysfunction, biochemical dysfunction, or structural alterations. There is some evidence to suggest that there are significant differences in the mode of TBI presentation based on etiology, but these differences still produce effects that are within a spectrum of those that can be seen in TBI irrespective of the etiology.15,16 Despite the debate, the NIH definition was crafted pragmatically to allow general acceptance. Initially TBI was broadly divided into mild, moderate, and severe using the wellestablished Glasgow Coma Scale (GCS) as an acute metric.15 While this method seems straightforward given the objective nature of the GCS, this criterion has three main shortcomings. Firstly, most of the individuals with GCS scores less than 13 have some form of severe TBI, meaning the remaining individuals are compressed into a fairly tight range of 13 15 with the vast majority of these being 15. As such the numerical value of the GCS seems ideally suited to distinguish severe from mild or moderate TBI, but this distinction is generally clinically apparent. Beyond that, the scale provides little value for individuals with mild TBI. Secondly, the vast majority of individuals with mTBI do not receive a GCS at the time of injury. Hence, the value of any subsequent or “retrospective” GCS, especially days later, is suspect at best. Finally, individuals with mTBI have a range of sequelae and different outcomes despite having a GCS of 14 or 15; as such, the value does little to distinguish patients on the basis of signs and symptoms that characterize the functional pathology.
I. DEFINING MILD TBI
THE NIH DEFINITION
5
THE NIH DEFINITION A person with a mild TBI may remain conscious or may experience a loss of consciousness for a few seconds or minutes. Other symptoms of mild TBI include headache, confusion, lightheadedness, dizziness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, a change in sleep patterns, behavioral or mood changes, and trouble with memory, concentration, attention, or thinking.
This description incorporates three generally accepted definitions of mTBI that have been published over time.17 In 1993 the American Congress of Rehabilitation Medicine (ACRM) described mTBI as an alteration of brain function caused by an external force with one of more to the following: (1) loss of consciousness (LOC) of 0 30 minutes; (2) posttraumatic amnesia (PTA) lasting 0 24 hours; (3) focal neurologic deficits may or may not be transient; and (4) alteration of mental state at the time of the accident (confusion, disorientation, slow-thinking).18 In 2003, the Centers for Disease Control and Prevention (CDC) offered a slightly less specific classification in which an individual must have any period of observed or self-reported transient confusion, disorientation, or impaired consciousness around the time of a head injury with LOC lasting 0 30 minutes.19 In 2009, the Department of Defense (DoD) established guidelines similar to the ACRM guidelines, but added that the alteration of consciousness (AOC) lasts less than 24 hours.20 The DoD updated this definition in 2016 and defined mTBI as: “traumatically induced structural or physiologic disruption of brain function as a result of an external force with new onset or worsening of at least one of the following: loss or decreased level of consciousness, (LOC , 30 minutes, AOC ,24 hours), PTA (,1 day), alteration in mental status (e.g., confusion, disorientation, etc.), Neurological deficit (weakness, loss of balance, sensory losses, etc.)." They added that the GCS should be 13 15 and structural imaging should be normal.21 To summarize colloquially, mild TBI is diagnosed by a documented directed energy event that results in the patient reporting symptoms or displaying nonlocalizing signs of being “not quite right.” Complicating these definitions of mTBI include the subcategories of “complicated mTBI” and concussion. Some investigators use the term “complicated mTBI” when the mTBI symptoms are accompanied by positive findings with radiologic imaging.22 24 The difficulty with this diagnosis is that imaging changes over time. The original definition of “complicated mTBI” relied on CT scans that showed abnormalities; there is some evidence that these individuals followed a course more similar to moderate TBI.23,24 Therefore, positive CT scan findings often shift diagnosis to the moderate TBI group. However, more modern imaging, including traditional MRI, fMRI, high Tesla MRI, and other scans, do detect abnormalities in some individuals and it is unclear whether these abnormalities have any longer term clinical or functional implications that distinguish them from symptomatic, but radiologically negative, patients. The term concussion is often used synonymously with mTBI. It is likely the case that concussion is simply a type of mTBI. While it is usually on the milder side of the spectrum, the short-term and long-term consequences provide little basis for distinguishing between these terms. The diagnostic criteria for concussion in athletes has been examined by a group of experts meeting every other year who have published updated guidelines after each of these meetings.25,26
I. DEFINING MILD TBI
6
1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
While the diagnosis of mTBI and concussion remain difficult to differentiate, postconcussion syndrome has an acceptable definition provide for the International Classification of Diseases 10th edition (ICD-10).27 This World Health organization-accepted medical definition requires the following: (1) The syndrome follows a head trauma, and (2) The individual present with at least three of the following eight symptoms: headache, dizziness, fatigue, irritability, difficulty concentrating, memory impairment, insomnia, and intolerance to stress, emotion, or alcohol. Because this definition of concussion appears to be synonymous with mTBI, there seems to be little value in assigning this term only to the “mildest” cases until there is a more objective and precise way of making this determination. We must acknowledge that: the diagnosis of mTBI or concussion requires the presumption of a causal link to a documented traumatic event. The dilemma becomes most evident when a patient appears for a workman’s compensation examination, reporting a plethora of nonspecific symptoms that could indicate mTBI. The patient attributes the symptoms to an unwitnessed head-bump several weeks earlier. If one subjects the patient to a large battery of neurologic tests and advanced imaging, what is the likelihood that incidental chronic findings might be misattributed to an undocumented traumatic event? These considerations obviously mandate a healthy skepticism prior to asserting post hoc diagnoses from unknown cranially directed energy exposures. Although we can document signs and symptoms that appear after documented traumatic events, the observations of a similar clinical syndrome are insufficient to substantiate a causal claim regarding an unverified (or assumed) traumatic incident. The structure of symptom complexes in acute mTBI suggests that integrative, objective diagnosis should be tractable. For example, principal component analysis of a standard 22item symptom scale showed acute mTBI and control subjects differed by a posttraumatic migraine/headache symptom cluster, a dizziness/mild cognitive impairment symptom cluster, an emotional lability symptom cluster, a cervicogenic (neck pain fatigue malaise) symptom cluster, and nausea.28 Unfortunately, attempts to devise integrative approaches to overall objective diagnosis of mTBI signs have been complicated by several issues. Firstly, the symptom clusters do not unambiguously point to localized injury. Secondly, concerns have been raised about the accuracy of symptom self-reports, which seem to be inherently unreliable and unstable in patients with mTBI.29,30 For example, symptom reports may be exaggerated or understated (denial) for secondary gain, which can produce symptom complex component scores on both tails of the distributions in acute mTBI patients (Hoffer et al. PLoS One, symptom complex paper) Thirdly, the heterogeneous presentation of mTBI makes unified objective diagnostic criteria difficult to identify. The presentation can vary with small changes in the magnitude or direction of the force, by the subjects’ past medical and particularly, past head injury, history, and by a variety of other factors including anatomic and genetic differences. Fourthly, the manifestations of the mTBI change over time, based on external environmental and epigenetic influences that are independent of the trauma and, again, affect every individual differently. Fifthly, mTBI in an individual case may involve a number of parallel, but very small injuries, in more than one location in the brain or intracranial sensory organs Sixthly, home remedies, spontaneous compensation, and variations in treatment regimens complicate the subacute and chronic presentations. These factors may contribute to the conclusion that the trend of attempts to classify the disorder in terms of common objective features has been fraught with difficulty.15
I. DEFINING MILD TBI
REFERENCES
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Currently, there is no definitive path to make a “ground-truth” diagnosis of a mTBI without a validated, temporally proximate acute application of external force. The problem obviously becomes exacerbated as the latency increases between a suspected event and presentation of the patient. Criteria have been established by a variety of organizations, but there remains debate as to how best to apply these criteria. Moreover, there remains debate over what constitutes an “external force” and the latency between the event and onset of signs and symptoms. Most investigators agree that classifying TBI into mild, moderate, and severe is a highly imprecise medical classification system.15,31 These researchers and clinicians advocate a more deliberate and objective approach to diagnosis that takes into account temporal sequences of symptoms, objective neurological signs, the recovery trajectory, and long-term outcomes. As a pragmatic matter, there is no justification for eliminating the diagnostic term mTBI until better alternatives for differentiated diagnosis are available. We believe a reasonable diagnostic criterion is very similar to the most recent criteria proposed by the DoD/VA.21 Our “operational definition” is that an individual: (1) suffers an impact to the head; (2) has LOC (,30 minutes) or AOC (,24 hours); and (3) presents with one of the symptoms including, but not limited to, balance disorder, hearing disorder, headache, visual changes, alteration in mental status, and sleep disturbance. This diagnostic criterion seems to brings together the criteria proposed and listed above and is in concordance with general clinical practice. The difficulty in developing a definition for mTBI is magnified when attempting to utilize this definition for translational research. Research on animal models is vitally important to both develop new diagnostic and treatment algorithms, as well as to translate basic science findings into human use. Unfortunately, most rodent animal models seek to create a very homogenous pattern of injury, but are attempting to model a disorder that is very heterogeneous in humans.32 In addition, physical damage that would be termed severe in a humans produces only modest behavioral signs in rodent animal models. The ability to reproduce rodent analogues of human psychological and social impacts of mTBI are far from incontrovertible. This is certainly an area where a more precise definition based on the site of injury or neuropathological findings would be helpful. That being said, those set of conditions (site of injury, neuropathological findings, etc.) are likely to be just as heterogeneous in affected humans as the current symptom spectrum of mTBI, therefore, such precision may not allow for better translational research. No matter how it is defined, we believe that the term mTBI in particular and TBI in general must be “destigmatized.” Too often there is serious debate over whether an individual has “TBI” when it is clear that the individual had a blow to the head, suffered and AOC, and has symptoms. The individual clearly has a brain injury that should be labeled as “TBI.” This label implies nothing about short-term or even long-term consequences, nor should it be reserved for only a particular type of brain injury or particular class of individuals.
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1. WHAT IS MILD TRAUMATIC BRAIN INJURY?
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